Oligoadenylate synthetase 3 S381R gene polymorphism is associated with severity of EV71 infection in Chinese children

https://doi.org/10.1016/j.jcv.2018.01.015Get rights and content

Highlights

  • The carriage frequency of OAS3 S381R CC genotypes and the occurrence of C allele in severe EV71infected cases were significantly higher than in mild cases.

  • Severe cases had significant higher levels of IFN-γ in GC + GG genotypes compared to CC genotype.

  • Carrying C allele of the OAS3 S381R gene could be a susceptibility factor in the development of severe EV71 infection.

Abstract

Background

Oligoadenylate synthetase 3 (OAS3) is interferon-induced antiviral enzyme, playing a significant role in the innate immune response. Genetic polymorphism in OAS3 gene has been reported to be a susceptibility factor in many infected diseases, but evidence of its effect on enterovirus 71 (EV71) infection is still lacking.

Objectives

An attempt study was made to investigate whether genetic polymorphism of OAS3 S381R is associated with the severity of EV71 infection in Chinese children.

Study design

Retrospectively sumed up the clinical onsets and experimental results for 249 cases with EV71 infection (including 151 mild cases and 98 severe cases) and 243 controls. An improved multiplex ligation detection reaction (iMLDR) technique was carried out to analyze polymorphism in OAS3 S381R G/C gene for genetic association analyses. The plasma levels of IFN-γ were determined by enzyme-linked immunosorbent assays.

Results

The distribution of OAS3 S381R CC genotype (73.47%) and C allele (85.20%) in severe cases was markedly higher than in mild cases (45.70%, P < .01; 67.88%, P < .01). The blood IFN-γ levels of severe cases were significantly lower in CC genotype (131.66 ± 10.84 pg/mL) compared to GG (183.37 ± 24.50 pg/mL, p < .01) and GC genotype (168.48 ± 26.57 pg/mL, p < .01).

Conclusions

Carrying the C allele of the OAS3 S381R gene could be a susceptibility factor in the development of severe EV71 infection in Chinese children.

Section snippets

Background

Enterovirus 71 (EV71) is a positive-sense RNA virus belonging to species Enterovirus A, and is a member of family Picornaviridae. Since it was first isolated from stool specimen in a child with central nervous system in 1969, a large outbreak of EV71 infections have occurred across the Asia-Pacific region, causing great economic and social burden [[1], [2], [3], [4]]. Compared with other enteroviruses, EV71 can cause fatal neurological complications because of its neurotropism [5]. There is a

Objectives

In the present study, the purpose was (1) to investigate whether the OAS3 S381R gene polymorphism is associated with the susceptibility and severity of EV71 infection in Chinese children. (2) to evaluate whether the IFN-γ levels are correlated with OAS3 S381R gene polymorphism in patients with the severity of EV71 infection.

Subjects

We investigated 260 Chinese Han children with EV71 infection (137 males and 123 females) at the Pediatric Department of the Affiliated Hospital of Qingdao University and Qingdao Women & Children Hospital, China, between May 2013 and August 2015. A total of 243 children (128 males and 115 females) undergoing a health check-up in hospital were recruited as the control population during the same period. Of the EV71-infected patients, 11 children were excluded because of underlying diseases:

Baseline demographics and characteristics

In this study, we investigated a group of 249 EV71-infected patients (134 males and 115 females) aged from 0.5 to 13.8 years. There were 151 mild cases (80 males and 71 females, aged 4.85-5.83 years) and 98 severe cases (54 males and 44 females, aged 4.67–6.13 years). As shown in Table 1, no significant difference was observed in gender (P = .743) and age (P = .883) between mild and severe cases. However, compared to mild cases, severe cases had longer duration of fever days (P < .01), more

Discussion

EV71 infection can affect multiple tissues and organs, causing severe neurological complications. Severe cases caused by EV71 have higher morbidity and mortality, emerged as a serious global public health problem. Various factors can influence the different physical responses to the same infectious agent, including the virulence of the pathogen and the ability on the part of the host to resist infection. Host genetic factors are thought to influence the susceptibility to infection as well as

Funding

This work was financially supported by the National Natural Science Foundation of China (grant number 31640047), and technically helped by Genesky Biotechnologies Inc., Shanghai, China. The authors thank their patients for blood donation and agreement to participate in this study.

Ethics approval

All steps included in the study involving human participants obeyed the ethical standards of Ethics Review Committee of the Medical College of Qingdao University.

Competing interest

None to disclose.

References (34)

  • B.et al. Wang

    Enterovirus 71 protease 2Apro targets MAVS to inhibit anti-viral type I interferon responses

    PLoS Pathog.

    (2013)
  • P.S. Pathinayake et al.

    Innate immunity and immune evasion by enterovirus 71

    Viruses

    (2015)
  • A. Takaoka et al.

    Interferon signalling network in innate defence

    Cell. Microbiol.

    (2006)
  • A.J. Sadler et al.

    Interferon-inducible antiviral effectors

    Nat. Rev. Immunol.

    (2008)
  • L.B. Ivashkiv et al.

    Regulation of type I interferon responses

    Nat. Rev. Immunol.

    (2014)
  • D. Rebouillat et al.

    The human 2', 5'-oligoadenylate synthetase family: interferon-induced proteins with unique enzymatic properties

    J. Interferon Cytokine Res.

    (1999)
  • M.S. Ibsen

    The 2'-5'-oligoadenylate synthetase 3 enzyme potently synthesizes the 2'-5'-oligoadenylates required for RNase L activation

    J. Virol.

    (2014)
  • Cited by (9)

    • EV71 3C protease cleaves host anti-viral factor OAS3 and enhances virus replication

      2022, Virologica Sinica
      Citation Excerpt :

      It is particularly important to study the relationship between EV71 and innate immune system. Previous studies were limited to finding the association between OAS3 gene polymorphisms and the severity of EV71 infection (Tan et al., 2017; Liu et al., 2018). The effect of OAS3 against EV71 and the mechanism of EV71 escape were not reported.

    • Genome-wide association study identifies TPH2 variant as a novel locus for severe CV-A6-associated hand, foot, and mouth disease in Han Chinese

      2020, International Journal of Infectious Diseases
      Citation Excerpt :

      Several studies have investigated the susceptibility variants of HFMD in past years, but most of them were focused on EV-71 HFMD patients. For example, the C allele in S381R of OAS3 (oligoadenylate synthetase 3) was reported to increase the risk of severe EV71 HFMD in Chinese children (Liu et al., 2018). And rs11574129 and rs739837 polymorphisms in the VDR (vitamin D receptor) gene were demonstrated to be associated with the severity of EV-A71 HFMD (Li et al., 2019).

    • Association of CD14 rs2569190 G/A genetic polymorphism with the severity of enterovirus 71 infection in Chinese children

      2020, Virology
      Citation Excerpt :

      Although we collected patients infected with EV71 from 2012 to 2014, we still need to test the subtype of EV71 to ensure that all EV71-infected cases belong to the same subtype and exclude the effect caused by the variants of EV71 virus itself. In addition to this, the polymorphisms of HLA-A33, OAS3 and some cytokines have been shown to be associated with EV71 infection (Chang et al., 2016; Liu et al., 2018; Lv et al., 2013; Zhao et al., 2017). In a word, an increasing number of studies indicated that the polymorphisms of EV71 and host genes and the subgenotypes of EV71 were related to EV71 susceptibility and the severity of EV71 infection.

    View all citing articles on Scopus
    1

    Shared first authorship.

    View full text